This invention relates to a new chemical process, and to new chemical compounds useful as intermediates in said process. More particularly, it relates to a new chemical process for the preparation of penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo. Said new chemical process comprises oxidation of a 6-halopenicillanic acid, or ester thereof readily hydrolyzable in vivo, to the corresponding 1,1-dioxide, followed by dehalogenation. Said new chemical compounds useful as intermediates are 6-alpha-halopenicillanic acid 1,1-dioxides and esters thereof readily hydrolyzable in vivo.
Penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo are useful as beta-lactamase inhibitors and as agents which enhance the effectiveness of certain beta-lactam antibiotics when the latter are used to treat bacterial infections in mammals, particularly humans. Previously, penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo have been prepared from 6-alpha-bromopenicillanic acid, or ester thereof readily hydrolyzable in vivo, by debromination to give penicillanic acid, or ester thereof readily hydrolyzable in vivo, followed by oxidation to the 1,1-dioxide. Although the process of the present invention starts with a 6-halopenicillanic acid, or ester thereof readily hydrolyzable in vivo, and involves the steps of dehalogenation and oxidation, surprisingly it is found that, if the oxidation step is performed before the dehalogenation step, a better yield of product is obtained. See British patent application No. 2,000,138A, published Jan. 4, 1979; Belgian Pat. No. 867,859, granted Dec. 6, 1978; and West German Offenlegungsschrift No. 2,824,535, published Dec. 14, 1978 for details of methods of preparing penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo.
6-alpha-Halopenicillanic acids have been disclosed by Cignarella et al., Journal of Organic Chemistry, 27, 2668 (1962) and in U.S. Pat. No. 3,206,469; hydrogenolysis of 6-alpha-halopenicillanic acids to penicillanic acid is disclosed in British Patent Specification No. 1,072,108.
Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1976) disclose: (a) the oxidation of 6,6-dibromopenicillanic acid with 3-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; (b) oxidation of methyl 6,6-dibromopenicillanate with 3-chloroperbenzoic acid to give a methyl 6,6-dibromopenicillanate 1,1-dioxide; (c) oxidation of methyl 6-alpha-chloropenicillanate with 3-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; and (d) oxidation of methyl 6-alpha-bromopenicillanate with 3-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides.
Clayton, Journal of the Chemical Society (London), Part C, 2123 (1969) discloses inter alia: (a) 6-alpha-iodopenicillanic acid and its methyl ester; and (b) 6,6-diiodopenicillanic acid and its methyl ester.